KR0133292B1 - Substituted 1,2,4-triazinediones, process for their preparation and composition containing thereof - Google Patents

Abstract

Novel substituted 1,2,4-triazinediones of the general formula I <IMAGE> in which R<1> represents heteroaromatic radicals bonded via carbon and which are optionally substituted, X represents O, S, SO or SO2, R<2> represents one or more, identical or different radicals of the group comprising hydrogen, halogen, nitro, alkyl, alkoxy, haloalkyl and haloalkoxy and R<3> represents hydrogen, optionally substituted alkyl, alkenyl, alkynyl or aralkyl, process for their synthesis and intermediates therefor. The compounds of the formula I are used for combating parasitic protozoa.

Description

Substituted 1,2,4-triazinedione, preparation method thereof and composition containing same

The present invention relates to novel substituted 1,2,4-triazinediones, methods for their preparation, intermediates for carrying out these methods and the use thereof.

The use of substituted 1,2,4-triazinedione to combat Coccidia is known. However, the action of these compounds is not satisfactory in all cases.

1. The present invention relates to substituted 1,2,4-triazinedione of novel general formula (1).

Wherein R ₁ represents an optionally substituted heteroaromatic radical bonded through carbon, X represents O, S, SO, or SO ₂ , and R ₂ represents hydrogen, halogen, nitro, alkyl, alkoxy, alkylthio , At least one same or different radical selected from the group consisting of halogenoalkyl, halogenoalkoxy and halogenoalkylthio, R3 represents hydrogen, optionally substituted alkyl, alkenyl, alkynyl or aralkyl.

2. The present invention

a) reacting a compound of formula (II), wherein X represents 0 or S, with a compound of formula (III)

b) reacting a compound of formula (Ia) with a compound of formula (IV) (except where R₃ is hydrogen) to produce a compound of formula (I) wherein R₃ is not hydrogen; or

c) reacting a compound of formula (I) in which X represents S with an oxidizing agent to produce a compound of formula (I) wherein X is -SO- or -SO₂-. It relates to a method for preparing substituted 1,2,4-triazinedione.

Wherein R 'represents an optionally substituted heteroaromatic radical bonded through carbon, X represents O, S, SO or SO2, and R2 represents hydrogen alone or hydrogen, halogen, nitro, alkyl, alkoxy, alkyl One or more identical or different radicals selected from the group consisting of thio, halogenoalkyl, halogenoalkoxy and halogenoalkyldio, R3 represents hydrogen, optionally substituted alkyl, alkenyl, alkynyl or aralkyl, and A is a radical Halogen, -O-SO₂-alkyl, -O-SO₂-halogenoalkyl, -O-SO₂-allyl, or -S-alkyl, -O-SO₂-halogenoalkyl, B represents halogen, -O-SO₂ -Alkyl, -O-SO2-aryl or -O-SO2-halogenoalkyl.

3. The present invention relates to a novel compound of formula (II).

Wherein X represents O or S, R2 represents one or more identical or different radicals selected from the group consisting of halogen, nitro, alkyl, alkoxy, alkylthio, halogenoalkyl, halogenoalkoxy and halogenoalkylthio, When X represents S, further hydrogen is represented, and R3 represents water, alkyl, alkenyl, alkynyl or aralkyl.

4. The present invention relates to a method for producing a novel chemical of formula (II) according to (3), characterized in that the compound of formula (V) is heated to decarboxylate.

Wherein X, R ² and R ³ are as defined in (3).

5. The present invention relates to novel compounds of the general formula (V).

Wherein X represents O or S, and R ² represents one or more identical or different radicals selected from the group consisting of halogen, nitro, alkyl, alkoxy, alkylthio, halogenoalkyl, halogenoalkoxy and halogenoalkylthio When X represents S, further hydrogen is represented, and R ³ represents hydrogen, alkyl, alkenyl, alkynyl or aralkyl.

6. The invention relates to a process for the preparation of novel compounds of formula (V) according to (5), characterized in that the compounds of formula (IV) are heated in the presence of an aqueous acid.

Wherein X, R ² and R ³ are as defined in (3), R ⁴ represents radical —CN or R ³ —CONCOOR 5 and R 5 represents optionally substituted alkyl or aryl.

7. The present invention relates to novel compounds of the general formula (VI).

In the above formula, X, R2, R₃ and R 'are as defined in (6).

8. The present invention relates to a process for preparing the novel compound of formula (VI) according to (7), characterized in that the compound of formula (VII) is heated in the presence of a base.

Wherein X, R ₂ , R ₃ and R _VII are as defined in (7), R ₆ represents alkyl or optionally substituted aryl, and R ₇ represents hydrogen or its substituted -C-alkali or -C-aryl Indicates.

9. The present invention relates to a new compound represented by the following general formula (VII).

If the formula, X, R₂, R₃, R₄ , R 5 and R ₇ are as defined in (8), R ₇ is H, or represent X represents S, R₂ may represent a hydrogen further.

10. The present invention is characterized in that the compound of formula (VII) is first diazotized using alkali nitrite in the presence of an aqueous inorganic acid, and then reacted with the compound of formula (VII). It relates to a method for producing a novel compound of general formula (IV).

Wherein X, R ₂ , R ₃ , R₄, R ₅ and R ₇ are as defined in (9). Compounds of formula (I) are thiazolyl, oxazolyl, benzothiazolyl or benzoxazolyl wherein R 'is each optionally substituted by harolgen, alkyl, cyano, nitro, O-alkyl, S-alkyl or halogenoalkyl , X represents O or S, R 2 represents halogen or C _1-6 -alkyl and R 3 represents hydrogen or C ₁ -C ₄ -alkyl, in particular methyl.

Particularly preferred compounds of formula (I) are those in which X represents O and R 'represents C1-4-alkyl (particularly methyl), C1-4-halonoalkyl (particularly trifluoromethyl), halogen (particularly Chlorine, bromine or fluorine), nitro, CN, amino, C1-4-alkylamino, C1-4-halogenoalkylamino, alkamino, C1-4-alkoxy (particularly methoxy), C1-4-halogeno Alkoxy (particularly trifluoromethoxy), C1-4-alkylthio (particularly methylthio) and C1-4-halogenoalkylthio (particularly trifluoromethylthio), C1-4-alkylsulfonyl (particularly Methylsulfonyl) and thiazolyl, benzothiazolyl or benzoxazolyl optionally substituted by C1-4-halogenoalkylsulfonyl (particularly trifluoromethylsulfonyl), wherein R2 is hydrogen, halogen (especially , Chlorine or bromine) or C1-4-alkyl (particularly methyl).

Very particularly preferred compounds of formula (I) represent thiazolyl or benzothiazolyl, wherein X represents O and R 'is optionally substituted by chlorine, methyl or trifluoromethyl, respectively, and R2 is hydrogen, methyl or chlorine. At least one radical selected from the group consisting of R 2 represents at least one radical selected from the group consisting of hydrogen, methyl or chlorine, and R 3 represents hydrogen.

Individual compounds that may be mentioned are as follows.

In addition, the following compounds may further be mentioned.

In method 2) 2- (3,5-dichloro-4-hydroxyphenyl) -1,2,4-triazine-3,5 (2H, 4H) dione is used as compound (II) and 2-6 If dichlorobenzothiazole is used as the compound of the general formula (III), the process can be described by the following formula.

Compounds of general formula (II) wherein R 2 and R 3 are represented by hydrogen are known. J Slouka, Acta Unio Palacki Olomuk. Fac. Rerum. Nat 1984 (Chem 23), 39-45; C.A. 102 203946c].

The compounds of formula (II) in which R2 represents radicals other than hydrogen are novel. Preferably, mention may be made of compounds of the general formula (II) in which R 2 and R 3 have the meanings mentioned preferably in the compounds of the general formula (I). The following novel compounds of general formula (II) may be mentioned. The following novel compounds of general formula (II) may be specifically mentioned.

Substituted heterocycles of formula (III) are known or can be prepared analogously to known methods. See Beilsteinvol. 27; Katrizky and Rees, Comrehensive Het. Chem, Col. 6. 1984].

The compound has the meanings mentioned above as being preferred for the compound of general formula (I). The following compound of general formula (III) can be mentioned specifically.

The reaction is preferably carried out using a diluent.

Suitable diluents are substantially all inert organic solvents. They are preferably aliphatic and aromatic optionally halogenated hydrocarbons, benzene, ligroin, benzene, toluene, xylene, methylene, chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, ethers such as diethyl ether and Dibutyl ether, glycol dimethyl ethyr and diglycol dimethyl ether, detrahydrofuran and dioxane), ketones (e.g. acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isoyl ketone), esters (e.g. methyl Acetates and ethyl acetate), nitriles (e.g. acetonitrile and propionitrile), amides (e.g., dimethylformamide, dimethylacetamide and N-methyl-pyrrolidone) and dimethyl sulfoxide, tetramethylene sulfone and hexamethyl Phosphoric triamides.

The reaction is carried out in the presence of an inorganic or organic acid acceptor.

Examples of receptors that may be mentioned are: alkali metal hydroxides (e.g. sodium hydroxide and potassium hydroxide). Alkaline earth metal hydroxides (e.g. calcium hydroxide), alkali metal carbonate saliva alkoxides (e.g. sodium carbonate and potassium carbonate, sodium methoxide and potassium methoxide or sodium ethoxide and potassium ethoxide) and aliphatic, aromatic or heterocyclic amines ( Examples: triethylamine, pyridine, 1,5-diazabicyclo- [4.3.0] -non-5-ene (DBN), 1,8-diazabicyclo- [5.4.0] -undec-7-ene (DBU) and 1,4-diazabicyclo- [2.2.2] -octane (DABCO)].

The reaction is carried out at temperatures between 50 and 200 ° C., preferably between 80 and 160 ° C. under atmospheric or elevated pressure. Preference is given to performing at atmospheric pressure.

The process is carried out by combining equimolar amounts of the compounds of formulas (II) and (III) with heating in one of the mentioned diluents. After completion of the reaction, the reaction mixture is acidified with dilute inorganic acid (eg hydrochloric acid) and the resulting precipitate is filtered off and washed.

In the method 2b) for preparing a compound of formula (I) wherein R3 is not hydrogen, 2- [4- [2'-benzothiazolyloxy] phenyl] 1,2,4-triazine-3,5- ( If 2H, 4H) -ion is used as the compound of the general formula (1a) and methyl iodide is used as the compound of the general formula (IV), the process can be described by the following formula.

Compounds of formula (1a) are novel and are prepared as described in method 2a).

Compounds of formula (IV) are known or can be prepared by known methods. Methyl iodide and ethyl bromide may be mentioned in particular.

The process is carried out by reacting a compound of formula (1a) with a compound of formula (IV) in the presence of a base and a diluent. It is also possible to use as diluent any inert organic solvent used to carry out method 1a).

The process is carried out in the presence of a base. Preferred bases which may be mentioned are alkali metal hydroxides such as sodium hydroxide, alkali metal alkoxides such as sodium methoxide or potassium butoxide, metal hydrides such as sodium hydride or organic bases such as 1-8. Diazabicyclo [5.4.0] -undec-7-ene (DBU).

The process is carried out at temperatures between 20 and 140 ° C. under atmospheric pressure. The reaction is carried out by combining an animal amount of the compound of the general formula (1a) with a base, adding an equivalent amount of the compound of the general formula (IV) to the mixture, and then heating to the reaction temperature.

In method 2c), wherein X is SO or SO2, a compound of formula (I) is prepared. In 2-C4, 2- [4 [-(2 '(benzoxazolylthio) phenyl] -1,2,4-triazine-3, If 5 (2H, 4H) -dione is used as the compound of the general formula (I), the process can be described by the following formula.

The process is carried out by treating a compound of formula (I) wherein X is S with an oxidant in the presence of a diluent. The following compounds are preferably used as oxidants; Hydrogen peroxide and other inorganic peroxides such as sodium peroxide, organic peroxide acids such as m-chlorofebenzoic acid and iodine-oxygen compounds such as sodium metaperiodate.

Diluents which can preferably be used are as follows: alcohols such as methanol, organic acids such as acetic acid and ketones such as acetone. Halogenated hydrocarbons such as thichloromethane or acid anhydrides such as acetic anhydride are also used. Oxidation is carried out at temperatures of 0 to 120 ° C. Preference is given to performing under atmospheric pressure.

The amount of oxidant can vary from 1 mol to 10 mol. The reaction is carried out by stirring the mixture of formula (I), wherein X is S, for several hours at the reaction temperature mentioned in one of the oxidants mentioned and one of the diluents mentioned above.

In method 4) for preparing the compound of formula (II), 2- (3-methyl-4-hydroxyphenyl) -1,2,4-triazine-2,5 (2H, 4H) -dione-6 If carboxylic acid is used as the compound of formula (V), the process can be described by the following formula.

Compounds of formula (V) wherein X represents O and R 2 and R 3 represent hydrogen are known [J. Slouka, C. A. 102, 203946 k]. Compounds of formula (V) wherein R2 is not hydrogen are novel.

The novel compounds of general formula (V) are known in the art, for example, in DE-OS 2,358,851; J. Slouka, Mh. Chem. 96, 124 (1965). The individual compounds of formula (V) which may be mentioned are as follows;

Decarboxylation is optionally carried out in the presence of an inert organic diluent. Diluents include aliphatic and aromatic optionally halogenated hydrocarbons (e.g. nona, decane, dodecane and xylene), ethers (e.g. ethylene glycol monobutyl ether and diethylene glycol dibutyl ether), sulfoxides (e.g. dimethylsulfoxide) And sulfones such as tetramethylenesulfone.

The reaction may also be carried out in the presence of mercapto group-containing carboxylic acids such as mercapto acetic acid or thiosalicylic acid.

The reaction is optionally carried out at 150 to 300 ° C., preferably 160 to 250 ° C., in the presence of a mercapto group-containing carboxylic acid such as mercapto-acetic acid. Especially at a temperature of 180 to 210 ° C.

The reaction is carried out at atmospheric pressure. The compound of formula (V) is heated, dissolved or suspended in the substance or in the individual diluents.

2- (3-methyl-4-hydroxyphenyl) -6-cyano-1,2,4-triazine 3,5 (2H, 4H) dione in method 6) for preparing the compound of formula (V) If is used as a compound of the general formula (VI), the reaction can be described by the following formula.

X is 0 and R 'represents CN and compounds of formula (VI) are known. Slouka, C. A. 102, 203946 K]. Compounds of formula (VI) wherein R 2 is not hydrogen are novel.

The novel compounds of formula (VI) can be prepared by known methods [J. Slouka, Mh. Chom. 96. 134 (1965); DOS 2,358,851.

The compounds of the general formula (V) which may be mentioned are as follows.

Hydrolysis is carried out under acidic conditions. Acids which can be used include inorganic acids (eg mixtures of hydrochloric acid, hydrobromic acid, sulfuric acid and inorganic acids) and organic acids (eg acetic acid or propionic acid).

The reaction is carried out at a temperature of 80 to 120 ° C. Perform at atmospheric pressure.

The compound of formula VI is dissolved in 10-30 times the volume of acid or acid mixture and heated until hydrolysis is complete.

In method 8) for preparing the compound of formula (VI), ethyl N-[[[cyano (3-methyl-4-hydrocyphenyl) -hydrazinylidene methyl] -carbonyl] -carbamate When used as a compound of formula (IV), reaction can be described by the following formula.

The compound of general formula is new. These are known methods [J. Slouka, Mh. Chem. 94. 258 (1963).

The individual formulas which may be mentioned are as follows.

The process is optionally carried out by heating the compound of formula IV in the presence of a solvent and a base.

The solvent mentioned for preparing compound (I) is used as the solvent and the base. Alcohols (eg ethanol) or organic acids (eg glacial acetic acid) are also used as particularly preferred organic solvents.

Particularly preferred bases are hydroxides and acetates of alkali or alkaline earth metals such as NaOH or sodium acetate and potassium acetate.

The reaction is carried out under atmospheric pressure at a temperature of 70 to 150 ° C, preferably 70 to 100 ° C.

The base used is used in molar excess of 10 to 80%. After completion of the ring closure reaction, the reaction mixture is preferably acidified with dilute inorganic acid (eg hydrochloric acid) and the resulting product is filtered off as a solid.

In method 10) for preparing a compound of formula (VII), 3-methyl-4-hydroxyaniline is used as the compound of formula (VII) and ethyl cyanoacetylurethane is used as the compound of formula (VII) If used, the reaction can be described by the following equation.

Compounds of formula (VIII) and (VIII) are known or can be prepared analogously to known methods.

The process is optionally carried out by reaction with NaNO ₂ and a concentrated inorganic acid (eg HCI) of general formula aniline in the presence of a diluent. Diluents include water miscible diluents such as alcohols such as methanol and ethanol, organic acids such as acetic acid and formic acid, glycol ethers such as monomethylglycol ether, nitriles such as acetonitrile or dimethylsulfoxide.

The diazonium salt thus produced is reacted in situ with a compound of the general formula (e.g., malonyldiurethane or cyanoacetylurethane) in the presence of a base. Bases used are hydroxides and carbonates of alkali and alkaline earth metals and acetates of sodium, potassium and ammonium.

It is also possible to use organic bases such as pyridine or triethylamine. Diazolation is carried out under atmospheric pressure at a temperature of 0 to 10 ° C. Addition of the compound of general formula (iii) is performed at 5-20 degreeC. Aniline and nitrite are reacted in an equimolar amount in an excess, preferably two to three times molar amount of acid. The CH acid compound is added in 0-30% molar excess, preferably 10% molar excess. Base is added in 1.5-2.5 fold molar excess.

The coupling product of the diazonium salt and the CH acid compound is insoluble in the reaction medium and can be separated as a solid.

The process can also be carried out in such a way that the compound of formula (VI) is produced directly without separation of the compound of formula (VII). For this purpose, the diazolation of general formula aniline and the reaction with urethanes of general formula are carried out in a diluent suitable for ring closure reaction. When diazotization and coupling are carried out, the reaction mixture is heated and the triazinedione of formula (VI) is separated.

As diluents, mention may be made of the following: alcohols such as methanol and ethanol;

The ring closure allows the reaction mixture to reach about 80 to 120 ° C. Preferably by heating to about 80 to 100 ° C.

To prepare the compound of formula (VI), work up as described further above.

The present active compounds are suitable for breeding, breeding, zoo, experimental, test and pet animals, and are suitable for combating the protozoa that occur during animal breeding and animal breeding, and have a desirable toxicity against warm-blooded animals. These compounds are active and resistant to all multi- or canine stages of pest growth, and generally also to sensitive strains. Regression of parasitic protozoa lowers disease mortality and harvest reduction (e.g., decreases in the production of meat, milk, wool, hides, eggs, honey, etc.), resulting in more economical and more convenient animals by using active compounds. Mathematics becomes possible.

Parasitic protozoa includes the following: Mastigophora: Trypanosomatidae, for example tripanosoma b. Trypanosoma b.brucei, T. B. gambiense, T. ratio. Rhodesiense, T. Congolense, T. Cruzi, T. Evansi, T. Equinum, T. Lewisi, t. Percae, tee, simiae, tee. Vivax], Leishmania brasiliensis, L, L. donovani, L. vivax. Tropica, for example trichomonadidae, for example Giardia lamblia, rats. G. canis. Sarcomastigophora (Rhizopoda): an invertebrate); Entamoebidae [e.g., Entamoeba histolytica], Hartmanellidae [e.g. : Acanthamoeba species, Hartmanella species], Apicomplea (sporozoa) spores: Eimeridae, e.g. Cerbulina (Eimeria acervulina), L. A. adenoides, two. Alabamensis, e. Anatis, lice, anseris, lice. Arloingi, Lee. Ashata, this. Auburnensis, E. Bovis, two. Brunetti, Lee. Canis, two. Chinchillae, e. Cluperarum, e. Columbae, e. Contorta, e. Crandalis, E. Dabliech, Lee. Dispersa, e. Ellipsoidales, lice, falciformis, lice. Faurei, two. Flavescens, e. Gallopavonis, 2 Hagani, this. Intestinalis, E. Iroquoina, Lee. Irresidua. this. Lababeana, L. Leucariti, E. Magna, tooth, maxima, tooth. Media. this. Melcagridis, meleagrimitis, lice. Mitis. this. Nacatrix, Lee. Ninakohlyakimovae, lice, ovis, lice. Parva, Lee. Pavonis, Lee. Perforans, E. pasani. E. pyriformis, E. Praecox, E. Residua, two. Scabra, spec., Lice. Stiedai, this. Suis, this. Tenella, yi. Truncata, two. Truttae, two. Zuernii, Giob-idium species, Isokspora belli, child. I. canis, child. Felis. children. Ohioensis, child. Rivolta, child, species, child. Suis, cystisospora, species. Cryptosporidium species; Toxoplasmadidae, for example Toxoplasma gondii: Sarcocystidae, for example Sarcocystis bovicanis, S, bobihominis (S. S. bovihominis), S. Obikanis, S. obifelis, S. Bell. s. Suihominis: Leucozoidae, for example Leucozytozoon simoondi; Plasmodiidae, for example Plasmodium berghei, P. falciparum, blood, malariae, blood. Obale. P.vivax, p. Species: Piroplasmea, for example Babsia argentina, B.. Bovis, rain. Canis, rain. Bell. Theileria parva, Teireria spp .; Adeleina, for example Hepatozoon canis, H species, Myxospora and Microspora, for example Glugea species, Noksema species. Pneumocystis carinii and Ciliophora (Ciliata: ciliary): Valantidium coli, Ichthiophthirius species, Trichodina species , Epistylis species.

In addition, the compounds according to the invention can be used in various fish parasites belonging to the parasitic (worms), especially sucking worms (larvae, monophytes), for example, Gyrodactylus spp. It is active against Dactylogyrus species, Pseudodactylogyrus species, Diplozoon species.

Breeding and petting animals include mammals such as cattle, horses, sheep, pigs, goats, camels, buffaloes, donkeys, rabbits, deer (fallw-deer), reindeer and furry animals (e.g. minks, chinchillas, raccoons) ); And birds such as chickens, geese, turkeys, ducks, pigeons, and domestic and zoo breeding birds. Also included are commercial fish.

Laboratory and test animals include mice, rats, guinea-pigs, golden hamsters, dogs, and cats. Pet animals include dogs and cats. Administration can be both prophylactic and therapeutic. The active compound is administered intestinally, parenterally, directly through the skin or through the nose or in the form of a suitable formulation.

The active compound is administered intestinally, parenterally, directly into the skin or through the nose or in the form of a suitable formulation.

Intestinal administration of the active compounds may be carried out orally, for example, in the form of powders, suppositories, tablets, capsule pastes, drinks, granules, drunks, bolus, drug combination feed or beverages. do. Skin administration can be effected, for example, by dipping, spraying, bathing, washing, pouring-on and spotting-on and dusting. In form. Parenteral administration is carried out, for example, in the form of injections (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implantation.

Suitable formulations are as follows:

Solutions such as injectable solutions, oral solutions, diluted orally administered concentrates, solutions for use in the skin or body cavity, pore-on formulations and gels; Emulsions and suspensions for oral or dermal administration and injection; Semi-solid formulations; Formulations in which the active compound is treated in an ointment base or in an oil-in-water or water-in-oill emulsion base; And solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses and capsules; Aerosols and inhalants, and active-compound-containing shaped articles. Injectable solutions are administered intravenously, intramuscularly subcutaneously. Injectable solutions are prepared by dissolving the active compound in a suitable solvent and optionally adding additives such as solubilizers, acids, bases, buffer salts, antioxidants and preservatives. The solution is sterile-filtered and sealed.

Solvents that may be mentioned include physiologically acceptable solvents such as water, alcohols such as ethanol, butanol, benzyl, alcohols and glycerol, hydrocarbons, propylene glycol, polyethylene glycol, N-methylpy There is rolidone and mixtures thereof.

In addition, the active compounds may optionally be dissolved in physiologically acceptable vegetable or synthetic oils suitable for injection.

Solubilizers that may be mentioned include solvents which promote dissolution of the active compound in the main solvent or prevent its precipitation, for example polyvinylpyrrolidone, polyoxyethylated castor oil and polyoxyethylated sorbitan Esters.

Preservatives include benzyl, alcohols, trichlorobutanol, p-hydroxybenzoic acid esters and n-butanol.

Oral solutions are administered directly. Concentrates are diluted orally before administration to oral administration. Oral solutions and concentrates are prepared as described above in an injectable solution that may dispense with sterile treatment.

Solutions for use on the skin are applied by pouring, spreading, rubbing, spraying, spraying, or dipping, bathing or washing the skin over it. These solutions are prepared as described above in solution for injection.

It may be advantageous to add a midpoint to the formulation. The midpoints are: inorganic thickeners such as bentonite, colloidal silica and aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohol and copolymers thereof, acrylates and methacrylates.

Gels are applied or applied to the skin or introduced into the body cavity. The gel is prepared as described in the injectable solution by the addition of sufficient thickener to produce a transparent substance having the same concentration as the ointment. The thickeners mentioned above are also used as thickeners. Pore-on formulations are poured or sprayed onto a limited area of the skin by a method that allows the active compound to penetrate the skin to act systemically or to be dispersed over the body surface.

Pore-on formulations are prepared by dissolving, suspending or emulsifying the active compound in a suitable skin-miscible solvent or solvent mixture. In addition, auxiliaries (such as colorants, absorbent-promoting substances, antioxidants, light blockers and adhesives) are optionally added,

Solvents that may be mentioned include water, alkanols, glycols, polyreylene glycol, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenyl ethanol and phenoxy ethanol, esters such as ethyl acetate Butyl acetate and benzine benzoate), ethers such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether and diethylene glycol mono-butyl ether), ketones such as acetone and methyl ethyl ketone, aromatic and / or Aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone or 2-dimethyl-4-oxy-methylene-1,3-dioxolane.

Colorants are all colorants that can be dissolved or suspended that are acceptable for use in animals.

Absorption-promoting substances include, for example, DMSO, sparse oils such as isopropyl myristate, dipropyl glycol glycolargonate, silicone oils, fatty acid esters, triglycerides and fatty alcohols.

Antioxidants are sulfites or metabisulfates (eg potassium metabisulfite), ascorbic acid, butylhydroxytoluene, butylhydroxyanisole and tocopherol.

For light blocking, for example, a benzophenone or novantisolic acid-based substance. Adhesives are, for example, cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates or gelatin.

Emulsions can be administered orally, skin or by injection.

Emulsions are water-in-oil or oil-in-water.

They dissolve the active compound in a hydrophobic or hydrophilic phase and, with the aid of suitable emulsifiers and, if appropriate, additional auxiliaries such as colorants, absorption-promoting agents, preservatives, antioxidants, light blockers and viscosity-neutral substances Prepared by homogenization using a solvent of another phase.

Hydrophobic phases (oils) that may be mentioned are: paraffin oil, silicone oil, natural vegetable oils such as sesame oil, almond oil and castor oil, synthetic triglycerides such as caprylic / capric acid beagle triglyceride), chain length C ₈ - mixture of triglycerides of the ₁₂ plant fatty acid or other specially selected natural fatty acids, as the case may be, part of a saturated or unsaturated fatty acids containing a hydroxyl group glycerides mixture, or C ₈ / C Mono- and diglycerides of ₁₀ -fatty acid; Side chains of average chain length containing fatty acid esters (e.g. ethyl stearate, di-n-butyryl adipate, nucleosil laurate and dipropylene glycol pelargonate), saturated fatty alcohols of chain length C ₁₆ -C ₁₈ Esters of fatty acids, isopropyl myristate, isopropyl palmitate, caprylic / capric esters of saturated fatty alcohols of chain length C ₁₂ -C ₁₈ , isopropyl stearate, oleyl oleate, decyl oleate, Ethyl oleate, ethyl lactate, waxy fatty acid esters such as dibutyl phthalate, diisopropyl adipate and ester mixtures associated with diisoporophyll adipate, in particular fatty alcohols such as isotridecyl alcohol, 2- Octyldodecanol, cetyl stearyl alcohol and oleyl alcohol); And fatty acids such as oleic acid and mixtures thereof.

Affinity phases that may be mentioned include water, alcohols such as propylene glycol, glycerol, sorbitol and mixtures thereof.

Emulsifiers that may be mentioned are: non-ionic surfactants such as polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl Stearate and alkoxypolyglycol ethers); Amphoteric surfactants such as di-Na N-lauryl--iminodipropionate or lecithin; Anionic-active surfactants such as Na laurylsulfate, fatty alcohol ethersulfate and mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanol amine salts; Cation-active surfactants such as cetyltrimethylammonium chloride.

In addition, auxiliaries that may be mentioned are: viscosity-enhancing and emulsion-stabilizing materials such as carboxymethylcellulose, methyl cellulose and other cellulose and starch derivatives, polyarylates, alginates, gelatin, gum arabic, polyvinyl Pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyreylene glycol, wax, colloidal silica or mixtures of the materials mentioned.

Suspensions can be administered by oral, dermal or injection. They are prepared by suspending the splitting compound in an excipient liquid, optionally with the addition of additional auxiliaries such as juice agents, colorants, absorbent-toxins, preservatives, antioxidants or light blockers.

Wetting agents (dispersants) which may be mentioned are the surfactants mentioned further above.

Subsidies which may be mentioned are also those mentioned above.

Semi-solid formulations can be administered orally or skin. These formulations are distinguished from the suspensions and emulsions described above only by their higher viscosity.

To prepare a solid formulation, the active compound is mixed with a suitable excipient to form the desired form, optionally with the addition of an adjuvant.

Excipients that may be mentioned are all inert hyperphysically acceptable substances. Materials that can be used are inorganic and organic materials. For example, inorganic materials include sodium chloride, carbonates such as calcium carbonate, hydrogen carbonate, alumina, silica, clay, teamed or colloidal silica and phosphates.

Organic materials include, for example, sugars, cellulose, dietary foods and feeds such as milk powder, animal food, grain foods and pieces, and starch.

Adjuvants are preservatives, antioxidants and coloring agents already mentioned above.

Further suitable auxiliaries include lubricants and suspending agents (e.g. magnesium stearate, stearic acid, talc, bentonite and disintegration-promoting substances such as starch or crosslinked polyvinylpyrrolidone), binders such as starch, Gelatin or linear polyvinylpyrrolidone and anhydrous binders such as microcrystalline cellulose.

The active compound may also be present in the formulation with a synergist or other active compound.

Ready-to-use formulations contain a concentration of 10 ppm to 20% by weight, preferably 0.1 to 10% by weight, of the active compound.

Formulations which are diluted prior to administration contain the active compound in a concentration of 0.5 to 90% by weight, preferably 1 to 50% by weight.

In general, it has proven advantageous to administer about 0.5 to about 50 mg, preferably 1 to 20 mg, of active compound per kg of body weight daily to obtain effective results.

The active compounds may also be administered in conjunction with animal feed or beverages.

Feed and food products contain from 0.01 to 100 ppm, preferably from 0.5 to 50 ppm of the active compound in combination with a suitable edible material.

The above feeds and foodstuffs can be used for therapeutic and prophylactic purposes. The feed or foodstuff is a concentrate or premix containing a blend of 0.5-30% by weight, preferably 1-20% by weight of the active compound with an edible organic or inorganic excipient together with a conventional feed. Prepare by mixing. Edible excipients are, for example, corn wheat or corn and soybean wheat or inorganic salts, preferably containing a small amount of edible powder preventive oil, such as corn oil or legumes. In this case, the obtained premix can be added to the complete feed before feeding to the animal.

Examples of use in coccidiosis that may be mentioned are as follows;

In poultry, especially chicken, duck, goose and turkey, for example, for the treatment and prevention of spores, 0.1 to 100 ppm, preferably 0.5 to 100 ppm, of the active compound is mixed with a suitable edible substance, for example a nutritional feed. do. In some cases, the amount of the active compound may be increased, particularly when the receptor is highly resistant to the active compound. Correspondingly, it may be administered via a beverage.

In order to treat individual animals, for example, when treating sporesporosis or toxoplasmosis in mammals, it is preferred to administer from 0.5 to 100 mg of active compound per kg of body weight daily to obtain the desired result. However, the amounts mentioned may vary somewhat, not only depending on the body weight or method of administration of the test animal, but also on the condition of the animal and the form of each animal or formulation and the time or interval of administration of the active compound. Thus, in certain cases, even below the minimum amount mentioned above can be sufficiently treated, while in other cases it may exceed the stated upper limit. If more doses are given, it may be convenient to administer them several times throughout the day.

Example A

Sporesing of Chickens Chickens 9 to 11 days of age are treated with a potent viral strain, a disease pathogen of intestinal spores, such as Eberia acervulina, E. coli. E. maxima and Yi. Infected with 40,000 spore-forming oocytes from E.tenella.

Three days before infection and eight days after infection (end of test), the active compounds are mixed and administered to the animal feed at the indicated concentrations.

The number of oocytes in animal feces is measured using the McMaster Chamber. Englbrecht and coworkers Parasitologische Arbeitsmehoden in Medizin and Veterinarmedizin, verlag, Berlin (1965).

Dosages that completely or mostly prevent the clinical symptoms of oocytes and / or sporeworms, including lethality, are considered effective. Effective dosages are as shown in the table below:

Manufacturing Example

Example of method 2a)

Example 1

2- [4 [(4'-chloro-21-thiazolioxy] phenyl] -3,5 (2H, 4H) -dioxo-as-triazine

29 g (0,01 mol) of hydroxyfurylazauracil. 1.5 g (0.01 mol) of dichlorodiazole and 1.4 g (0.01 mol) of potassium carbonate are stirred under reflux for 2 hours in 20 ml of anhydrous DMF. The cooled reaction mixture is acidified with HCI and the precipitated product is suction filtered. After recrystallization from ethanol, 2.9 g (90% of theory) of thiazolyloxarylazauracil are obtained.

The following compounds are similarly prepared.

Example 2

2-[[(4'-chloro-5'-methyl) -2'-thiazolioxy] phenyl] 1,2,4-triazine-3,5 (2H, 4H) dione

Example 3

2- (4- (2-benzothiazolioxy) -phenyl) -1,2,4-triazine-3,5 (2H, 4H) -dione

Example 4

2- [4- [6'-chloro) -2'-benzothiazolyloxy] -3,5-dichlorophenyl] -1,2,4-triazine-3,5 (2H, 4H) -dione

II. Example of method 2b)

Example 5

2- [4-[(4'-Chloro) -2'-thiazolyloxy] phenyl] -3-N-methyl-3,5- (2H, 4H) -dioxo-1,2,4-triazine

2 g (6 mmol) of thiazolyloxyarylazaucil are dissolved in 20 ml of anhydrous DMSO, and 0,14 g (6 mmol) of sodium hydride are added. The mixture is stirred at room temperature for 20 minutes, then 1.3 g (9 mmol) of methyl iodide in 5 ml of DMSO are added under argon. The mixture is warmed to 50 ° C. and left for 3 hours at ionicity. The reaction mixture is then concentrated in vacuo and then water is added. Suction filtration of the precipitated solid yields 1,5 g (71% of theory) of the N-methyl compound.

Example of method 2c)

2- [4- [6'-Chloro) -2'-benzooxazolylsuloxyl] -3,5-dichloro-phenyl] -1,2,4-triazine-3,5 (2H, 4H) -dione

10 g (0,027 mol) of chlorobenzoxazolithiophenylazauracil are dissolved in a mixture of 200 ml of methanol and 100 ml of dichloromethane. The mixture is cooled to 10 ° C. and 4.6 g of m-chloroperbenzoic acid (85% concentration) is added at this temperature. After stirring for 10 hours at 10 ° C., the solvent is removed by stripping in vacuo and the residue is recrystallized from isopropanol. 8.5 g of sulfoxide (82% of theory) are obtained.

The following compounds are prepared analogously:

Example 6

2- [4- (2'-benzoxazolylsulfoxyl) -3,5-dichlorophenyl] 1,2,4-triazine-3,5 (2H, 4H) -dione

Example 7

2- [4- (2'-benzoxazolylsuloxyl) -3,5-dichlorophenyl] 1,2,4-triazine-1,2,4-3,5 (2H, 4H) -dione

Example 8

2- [4 '-(6'-chloro) -2'-benzoxazolisulfonyl] -3,5-dichlorophenyl] 1,2,4-triazine-3,5 (2H, 4H) -dione

8.8 g (0.02 mol) of chlorobenzoxazolylthiophenylazaucil are dissolved in 100 ml of glacial acetic acid and stirred for 18 hours under reflux with 40 mol of 30% hydrogen peroxide. After cooling, water is added and the precipitate is suction filtered. Recrystallization from isopropanol yields 6.9 g of sulfone (73% of theory).

The following compounds are prepared analogously:

Example 9

2- [4- (2'-benzoxazolylsulfonyl) -3,5-dichlorophenyl] 1,2,4-triazine-3,5 (2H, 4H) -dione

Example 10

2- [4- (2'-benzoxazolylsulfonyl) -phenyl] 1,2,4-triazine-3,5 (2H, 4H) -dione

III. To implementation of method 4)

IIIa)

2- (4-hydroxyphenyl) -1,2,4-triazine-3,5 (2H, 4H) -dione

34 g (0.137 mol) of carboxylic acid are heated to 170 ° C. in 34 ml of mercaptoacetic acid. After 1.5 hours, the mixture is cooled, water is added and filtered to yield 24 g of decarboxylation product (82% of theory).

The following compounds are similarly prepared.

IIIb) 2- (3,5-dichloro-4-hydroxyphenyl) -1,2,4-triazine-3,5 (2H, 4H) -dione

IIIc) 2- (3-methyl-4-hydroxyphenyl) -1,2,4-triazine-3,5 (2H, 4H) -dione

IIId) 2- (4-hydroxyphenyl) -3,5 (2H, 4H) -dione-1.2.4-triazine

19 g (0.076 mol) of carboxylic acid are heated under argon in a metal bath at 260-280 ° C. until gas evolution is complete. After cooling, the residue is recrystallized from ethanol. 10 g of azauracil (64% of theory) are obtained.

IV, Example 6)

IVa) 2- (4-hydroxyphenyl) -3,5 (2H, 4H) dioxo-1,2,4-triazine-6-carboxylic acid

30.1 g (0.13 mol) of cyanoazauracil are stirred under reflux for 14 hours in 1000 ml of HCI / glacial acetic acid (1: 1). After cooling, the mixture is concentrated, water is added to the residue, and the precipitated product is suction filtered. 19 g (59% of theory).

The following compounds are similarly prepared;

IVb) 2- (3,5-Dichloro-4-hydroxyphenyl) -1,2,4-triazine-3,5 (2H, 4H) -dione-6-carboxylic acid

IVc) 2- (3-Methyl-4-hydroxyphenyl) -1,2,4-triazine-3,5 (2H, 4H) -dione-6-carboxylic acid

V Example of Method 8)

Va) 2- (4-hydroxyphenyl) -3,5 (2H, 4H) -dioxo-6-cyano-1,2,4-triazine

43.8 g (0.158 mol) of hydrolazonocyanurethane and 8.5 g (0.213 mol) of NaOH are heated under reflux for 2 hours in 400 mol of anhydrous ethanol. The mixture is then cooled, acidified with hydrochloric acid and then concentrated in vacuo. The residue is stirred with water and the deposited precipitate is suction filtered. Drying this way yields 30,1 g (85% of theory) of cyanoazauracil.

Vb) 2- (3,5-dichloro-4-hydroxyphenyl) -6-cyano-1,2,4-triazine-3,5 (2H, 4H) -dione

Vc) 2- (3-methyl-4-hydroxyphenyl) -6-cyano-1,2,4-triazine

Ⅵ. Example of method 10)

VIa) ethyl N-[[[cyano (4-hydroxyphenyl) -hydrazinylidene] -methyl] carbonyl] carbamate

10 g (0.091 mol) of 4-hydroxyaniline is dissolved in 19.7 ml of concentrated hydrochloric acid and 200 ml of glacial acetic acid, and a solution of 6.4 g (0.092 mol) of sodium nitrite in 30 ml of water is added dropwise at 0? 5 占 폚. The mixture is stirred until a clear solution is formed, then a mixture of 14.3 g (0.092 mol) of cyano acetyl urethane and 21 g (0.25 mol) of sodium acetate is added and the mixture is stirred at 10 ° C. for 3 hours. The reaction mixture is concentrated in vacuo, the residue is stirred with water and the solid is filtered off with suction. This gives 19 g (75%) of product as microcrystalline yellow powder.

The following compounds are similarly prepared.

VIb) ethyl N-[[[cyano- (3,5-dichloro-4-hydroxyphenyl) -hydrazinylidene] methyl] carbonyl] -carbamate

VIc) ethyl N-[[[cyano- (3-methyl-4-hydroxyphenyl) -hydrazinylidene] methyl] carbonyl] -carbamate

VId) 2- (3,5-dichloro-4-hydroxyphenyl) -1,2,4-triazine-3,5- (2H, 4H) -dione

196 g (1,1 mol) of 2,6-dichloro-4-aminophenol are dissolved in 2.4 L of ethanol and 240 ml of concentrated hydrochloric acid. The solution is cooled to 6 to 10 ° C. and an equimolar amount of aqueous sodium nitrate solution is slowly added. The mixture is then stirred for 30 minutes and then 400 g sodium acetate and 172 g (1.1 mol) cyanoacetylurethane are added successively, and the mixture is then stirred at room temperature for 1 hour. Then it is heated under reflux for 2 hours, cooled and water is added. The precipitate is suction filtered, washed with dilute HCI and water to give 289 g (88% of theory) of cyan azauracil.

Claims (5)

Substituted 1,2,4-triazinedione of Formula (I):

Wherein R ¹ represents a substituted or unsubstituted heteroaromatic radical bonded through carbon, X represents O, S, SO or SO ² , and R ² represents hydrogen, halogen, nitro, alkyl, alkoxy, alkylthio , At least one of the same or different radicals selected from the group consisting of halogenoalkyl, halogenoalkoxy and halogenoalkylthio, R3 represents hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl or aralkyl. A method of preparing 1,2,4-triazinedione substituted with the following general formula (I), characterized by reacting a compound of the following general formula (II) with a compound of the following general formula (III);

Wherein R ¹ represents a substituted or unsubstituted heteroaromatic radical, bonded through carbon, X represents O, S, SO or SO 2, R 2 represents hydrogen, hydrogen, nitro, halogen, alkyl, Represents one or more identical or different radicals selected from the group consisting of alkoxy, alkylthio, halogenoalkyl, halogenoalkoxy and halogenoalkylthio, R ³ represents hydrogen, substituted or unsubstituted alkyl, alkenyr alkynyl or ar Al represents alkyl, and A represents halogen —O—SO 2 -alkyl, —O—SO 2 -aryl, —O—SO 2 -halogenoalkyl, —S-alkyl, —SO 2 -alkyl or —SO 2 -halogenoalkyl. A composition for eradication of parasitic protozoans, characterized by containing at least one substituted 1,2,4-triazinedione of the general formula (I) according to claim 1 in combination with an extender, a surfactant, or both. A process for preparing substituted 1,2,4-triazinedione of formula (I), characterized by reacting a compound of formula (Ia) with a compound of formula (IV):

Wherein R ¹ represents a substituted or unsubstituted helloaromatic radical bonded through carbon, X represents O, S, SO or SO ² , and R ² represents hydrogen or hydrogen, nitro, halogen, alkyl , At least one of the same or different radicals selected from the group consisting of alkoxy, alkylthio, halogenoalkyl, halogenoalkoxy and halogenoalkylthio, R ³ is substituted or unsubstituted alkyl, alkynyl or aralkyl, B Represents halogen, —O—SO 2 -alkyl, —O—SO 2 -halogenoalkyl, or —O—SO 2 -aryl. Reacting a compound of formula (I) in which X represents S with an oxidizing agent so that substituted 1,2,4-triazinedione of formula (I) in which X is -SO- or -SO₂- Manufacturing method;

Wherein, R ¹ is bonded via a carbon, a substituted or represents a Hello aromatic radical is unsubstituted, R ² represents a hydrogen, or hydrogen, nitro, halogen, alkyl, alkoxy, alkylthio, halogenoalkyl, halogeno One or more identical or different radicals selected from the group consisting of alkoxy and halogenoalkylthio, R ³ represents hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl or aralky.